I. Field of the Invention
The present invention relates generally to the fields of enzymology and biochemistry. More particularly, it concerns the inhibition of the memapsin 1 protease and the treatment of memapsin 1-related diseases, including diabetes.
II. Description of Related Art
At the turn of this century 171 million individuals were estimated to have diabetes in the world, and this is expected to increase to 366 million by 2030 (Wild et al., 2004). Currently, 25.8 million people in the United States have diabetes. Therefore, diabetes represents a major illness and development of new effective treatments is of great importance.
About 90% of diabetes cases are Type 2 diabetes which is characterized by hyperglycemia resulting from both the reduction of the pancreatic beta-cell functions and mass, which causes an insufficient insulin production, and an increase of insulin demand associated with insulin resistance (Kahn et al., 2009). Thus, clinical interventions to increase beta-cell functions and mass are attractive approaches for the treatment of Type 2 diabetes.
Tmem27, also called collectrin, is a 46 kDa type I transmembrane protein consisting an ectodomain, a transmembrane domain and an intracellular domain. Tmem27 is present in relatively large amount in the pancreatic beta cells (Akpinar et al., 2005) and has been shown to associate with beta cell functions and Type 2 diabetes (Altirriba et al., 2010). Genetic mutations of transcription factor Tcf1, which regulates Tmem27 expression, are known to cause a form of diabetes (Shih et al., 2001). Interestingly, overexpression of Tmem27 in pancreatic beta cells leads to increased beta-cell proliferation, cell mass increase (Akpinar et al., 2005), and improved glucose stimulated insulin secretion (Fukui et al., 2005).
The abundance of Tmem27 protein in beta cells is regulated by ectodomain cleavage, which leads to two cleavage products, a 25 kDa N-terminal fragment that is ultimately released into the extracellular space, and a 22 kDa C-terminal fragment anchored to the membrane and is rapidly degraded by gamma-secretase (Akpinar et al., 2005). The processing of Tmem27, which inactivates its activity, reduces the functions of Tmem27 and the inhibition of Tmem27 degradation results in up-regulating beta cell mass and functions. The protease that cleaves off the ectodomain of Tmem27 has only recently been identified to be memapsin 1, also known as BACE2 (Esterhazy et al., 2011). In this study, mice with functionally inactive memapsin 1 and insulin-resistant mice treated with a siRNA memapsin 1 inhibitor both displayed augmented beta cell mass and improved control of glucose homeostasis due to increased insulin levels. Interestingly, memapsin 1 is also involved in the trafficking of insulin receptor in the beta cells (Casas et al., 2010).